Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis Qiutan Yang1†*, Shi-Lei Xue2†, Chii Jou Chan3, Markus Rempfler1, Dario Vischi1, Francisca Mauer Gutierrez1, Takashi Hiiragi3, Edouard Hannezo2*, Prisca Liberali1,4* 1Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland 2Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria 3European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany 4University of Basel. Petersplatz 1, 4001 Basel, Switzerland †These authors contributed equally: Qiutan Yang, ShiLei Xue * Correspondence to: firstname.lastname@example.org ; email@example.com; firstname.lastname@example.org Abstract: Various tissues in 3D organoid culture form structures that recapitulate the in vivo organ morphologies and lead to organotypic functionalities. Intestinal organoids derived from single cells are able to pattern a crypt-villus domain and undergo crypt morphogenesis without the support from mesenchymal cells. However, the nature and coordination of forces driving organoid morphogenesis remains poorly characterized. Through light-sheet microscopy and large-scale imaging quantification, we demonstrate that, in mouse intestinal organoid development, crypt formation coincides with stark lumen volume reduction. We develop a 3D biophysical model of two-domain organoids, to computationally screen different mechanical scenarios of crypt morphogenesis. Combining this with live-imaging data as well as multiple mechanical perturbations, we show that actomyosin-driven crypt apical contraction and villus basal tension work synergistically with lumen volume reduction to drive crypt morphogenesis, and demonstrate in particular the existence of a critical point in differential tensions above which crypt morphology becomes robust to volume changes. Finally, we identified by single-cell RNA sequencing, and validated by pharmacological perturbations, that sodium/glucose cotransporter specific to differentiated enterocytes modulate lumen volume reduction via cell swelling in villus region. Altogether, our study uncovers the cellular basis of how fate modulates osmotic and actomyosin forces to coordinate robust morphogenesis and discuss the generality of these findings in vivo.
Friedrich Miescher Institut for Biomedical Research
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